The role of non-classical MHC class I molecules in immune responses to Mycobacterium tuberculosis infection

非经典 MHC I 类分子在结核分枝杆菌感染免疫反应中的作用

基本信息

批准号：
10402266
负责人：
Chyung-Ru Wang
金额：
$ 56.74万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-14 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10402266
关键词：
Activities of Daily Living Adoptive Transfer Animal Model Antigen Presentation Antigens Attenuated Autoimmune Diseases Bacterial Model Biological Assay Biological Response Modifiers CD8-Positive T-Lymphocytes CD8B1 gene Characteristics Development Elements Equilibrium Exhibits Flow Cytometry Frequencies Future Gene Expression Profile Generations Genetic Glycopeptides HLA G antigen Histocompatibility Antigens Class I Homologous Gene Host Defense Human Immune response Immunity Immunodominant Antigens Immunologic Memory In Vitro Individual Interruption KLRD1 gene Kinetics Knowledge Lead MHC antigen Mediating Memory Modeling Mouse Strains Mucous Membrane Mus Mutant Strains Mice Mycobacterium Infections Mycobacterium tuberculosis Mycobacterium tuberculosis H37Rv Mycobacterium tuberculosis antigens Peptides Phenotype Play Population Predisposition Preventive vaccine Property Proteins Pulmonary Pathology Qa-1 Antigen Receptor Activation Regulatory T-Lymphocyte Role Surface T cell regulation T cell response T memory cell T-Cell Activation T-Lymphocyte T-Lymphocyte Subsets T-cell receptor repertoire Thymus Gland Tuberculosis Vaccination Vaccines Virulent Virus Diseases Vitamin B Complex base cytotoxic CD8 T cells microorganism antigen mouse model mycobacterial novel peptide vaccination prevent protective efficacy receptor response transcriptome sequencing tuberculosis immunity vaccination against tuberculosis vaccination strategy vaccine candidate vaccine development vaccine strategy

项目摘要

PROJECT SUMMARY While current Mycobacterium tuberculosis (Mtb) vaccine development has primarily focused on CD4+ and MHC Ia-restricted CD8+ T cell responses, increasing evidence shows that non-conventional CD8+ T cells restricted by MHC Ib molecules can recognize diverse microbial antigens and contribute to protection against Mtb infection. For example, H2-M3, Qa-1/HLA-E, Qa-2/HLA-G, MR1, and CD1 have been implicated in the host immune response against Mtb in mice and/or humans. However, most of these studies have only examined the function of MHC Ib-restricted T cells during the primary response to Mtb infection. Given that several subsets of MHC Ib- restricted T cells exhibit "innate-like" T cell characteristics and undergo unique thymic selection, it is unclear whether and which MHC Ib-restricted CD8+ T cell population can mount a memory response during Mtb infection. Furthermore, some MHC Ib molecules also act as regulators of the immune responses aside from their role in antigen presentation. In particular, Qa-1 can regulate immune responses against Mtb through the interaction with inhibitory CD94/NKG2A receptors and regulatory CD8+ T cells. To better understand the diverse role of MHC Ib molecules play in immune responses against Mtb, this proposal seeks to determine whether the composition and function of MHC Ib-restricted CD8+ T cell subsets in the secondary response differs from the primary response, as well as how individual Qa-1-mediated regulatory mechanisms contribute to the immune response against Mtb. In Aim 1, we propose to compare the kinetics, function, and protective ability of MHC Ib- restricted CD8+ T cell responses during primary and secondary Mtb infection in mice, and evaluate the protective efficacy of vaccination with Qa-1/HLA-E-restricted Mtb peptides. We will use a novel vaccination and re- challenge model that allows for complete clearance of an attenuated Mtb strain prior to challenge with fully virulent Mtb to study memory responses. These studies will allow us to identify the dominant MHC Ib-restricted CD8+ T cells and the Mtb antigens they present during the secondary immune response, their ability to mediate protective immunity against Mtb, and peptide vaccination strategies to increase the frequency of these effector CD8+ T cells. In Aim 2, we propose to investigate the mechanisms by which Qa-1 regulates immune responses during Mtb infection, with a focus on how inhibitory CD94/NKG2A receptors and suppressive Qa-1-restricted CD8+ Tregs individually contribute to the regulation of T cell responses during Mtb infection. To study these mechanisms, we will use mouse strains with genetic interruption of Qa-1’s interaction with individual receptors. These studies will allow us to identify how Qa-1 is able contribute to the balance between effector and regulatory immune responses for better protective immunity against Mtb. The combined results from our studies will yield a better understanding of how MHC Ib molecules and MHC Ib-restricted T cells contribute to the overall immune response against Mtb, for the development of better future vaccine strategies.

项目摘要虽然目前的结核分枝杆菌（MTB）疫苗的开发主要集中在CD4+和MHC上 IA限制的CD8+ T细胞反应，越来越多的证据表明，非惯性CD8+ T细胞受限制 MHC IB分子可以识别潜水的微生物抗原，并有助于防止MTB感染。例如，在宿主免疫中隐含了H2-M3，QA-1/HLA-E，QA-2/HLA-G，MR1和CD1 在小鼠和/或人类中对MTB的反应。但是，这些研究中的大多数只检查了功能 MHC IB限制的T细胞的主要反应MTB感染。鉴于MHC IB的几个子集 - 受限制的T细胞表现出“先天性”的T细胞特征并接受独特的胸腺选择，这还不清楚 MHC IB限制的CD8+ T细胞种群是否可以在MTB感染期间安装内存反应。此外，除了它们在抗原表现。特别是，QA-1可以通过相互作用调节针对MTB的免疫反应具有抑制性CD94/NKG2A受体和调节性CD8+ T细胞。更好地了解潜水员的作用 MHC IB分子在针对MTB的免疫反应中发挥作用，该提案旨在确定是否是否 MHC IB限制的CD8+ T细胞子集的组成和功能与次级响应中的组成和功能不同于主要反应，以及单个QA-1介导的调节机制如何有助于免疫对MTB的反应。在AIM 1中，我们建议比较MHC IB-的动力学，功能和保护能力在小鼠初次和继发MTB感染期间，CD8+ T细胞反应受到限制，并评估受保护的疫苗对QA-1/HLA-E限制的MTB肽的功效。我们将使用一种新颖的疫苗并重新挑战模型，可以完全清除衰减的MTB菌株，然后才能完全挑战强大的MTB研究记忆反应。这些研究将使我们能够确定主要的MHC IB限制 CD8+ T细胞和它们在继发免疫反应期间存在的MTB抗原，它们的介导能力对MTB的保护性免疫力以及胡椒疫苗接种策略以增加这些效应器的频率 CD8+ T细胞。在AIM 2中，我们建议调查质量检查调节免疫反应的机制在MTB感染期间，侧重于抑制性CD94/NKG2A受体和抑制QA-1限制性 CD8+ Treg单独有助于MTB感染期间T细胞反应的调节。研究这些机制，我们将使用QA-1与单个接收器相互作用的遗传中断的小鼠菌株。这些研究将使我们能够确定QA-1如何能够为效应子与调节之间的平衡做出贡献免疫反应以更好地保护MTB的免疫力。我们研究的综合结果将产生更好地了解MHC IB分子和MHC IB限制的T细胞如何有助于总体免疫对MTB的反应，以制定更好的未来疫苗策略。